Synthesis of 11,12-dihydro benzo[c]phenanthridines via a Pd-catalyzed unusual construction of isocoumarin ring/FeCl3- mediated intramolecular arene-allyl cyclization: First identification of a benzo[c]phenanthridine based PDE4 inhibitor

Thirupataiah, B and Reddy, Sujeevan Gangireddy and Kumar, Jetta Sandeep and Mudgal, Jayesh and Mathew, Jessy Elizabeth and Shenoy, Gautham G (2020) Synthesis of 11,12-dihydro benzo[c]phenanthridines via a Pd-catalyzed unusual construction of isocoumarin ring/FeCl3- mediated intramolecular arene-allyl cyclization: First identification of a benzo[c]phenanthridine based PDE4 inhibitor. Bioorganic Chemistry, 97. pp. 1-17. ISSN 0045-2068

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Abstract

In spite of their various pharmacological properties the anti-inflammatory potential of benzo[c]phenanthridines remained underexplored. Thus, for the first time PDE4 inhibitory potential of 11,12-dihydro benzo[c]phenanthridine/benzo[c] phenanthridine was assessed in vitro. Elegant synthesis of these compounds was performed via a multi-step sequence consisting of a Pd-catalyzed unusual construction of 4-allyl isocoumarin ring and FeCl3-mediated intramolecular regio- as well as site-selective arene-allyl cyclization as key steps. The overall strategy involved Sonogashira coupling followed by isocoumarin and isoquinolone synthesis, then chlorination and subsequent cyclization to afford a range of 11,12-dihydro derivatives. One of these dihydro compounds was converted to the corresponding benzo[c]phenanthridine that showed concentration dependent inhibition of PDE4B affording an initial hit molecule. The SAR study suggested that 11,12- dihydro analogs were less potent than the compound having unsaturation at the same part of the ring

Item Type: Article
Uncontrolled Keywords: Isocoumarin; Benzo[c]phenanthridine; Pd-catalyst; FeCl3; PDE4
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 15 Oct 2020 06:24
Last Modified: 15 Oct 2020 06:24
URI: http://eprints.manipal.edu/id/eprint/155896

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